KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1

Acute liver failure (ALF) is characterized by the rapidly progressive deterioration of hepatic function, which, without effective medical intervention, results in high mortality and morbidity. Here, using proteomic and transcriptomic analyses in murine ALF models, we found that the expression of multiple splicing factors was downregulated in ALF. Notably, we found that KH-type splicing regulatory protein (KHSRP) has a protective effect in ALF. Knockdown of KHSRP resulted in dramatic splicing defects, such as intron retention, and led to the exacerbation of liver injury in ALF. Moreover, we demonstrated that KHSRP directly interacts with splicing factor 3b subunit 1 (SF3B1) and enhances the binding of SF3B1 to the intronic branch sites, thereby promoting pre-mRNA splicing. Using splicing inhibitors, we found that Khsrp protects against ALF by regulating pre-mRNA splicing in vivo. Overall, our findings demonstrate that KHSRP is an important splicing activator and promotes the expression of genes associated with ALF progression by interacting with SF3B1; thus, KHSRP could be a possible target for therapeutic intervention in ALF.

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Publication Details

Journal
Cell Death and Disease
Published
2024-08-26
DOI
https://doi.org/10.1038/s41419-024-06886-1
Citations
4
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.94

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article

KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1

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4 citations
Cell Death and Disease
RNA Research and Splicing
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article

KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1

Tian Xu, Zhinang Yin, Ying Xiang, Kejun Liu, Qian Fang, Xuejun Zhao, Guangbo Mei, R. Xiao, Hui‐Fen Dong, Mingxuan Li, Cheng Wang, Rui Zhou, Xiaoqing Li, Jiaxi Zhang, Pingping Xiao, Lihua Qu
article en
4 citations

Abstract

Acute liver failure (ALF) is characterized by the rapidly progressive deterioration of hepatic function, which, without effective medical intervention, results in high mortality and morbidity. Here, using proteomic and transcriptomic analyses in murine ALF models, we found that the expression of multiple splicing factors was downregulated in ALF. Notably, we found that KH-type splicing regulatory protein (KHSRP) has a protective effect in ALF. Knockdown of KHSRP resulted in dramatic splicing defects, such as intron retention, and led to the exacerbation of liver injury in ALF. Moreover, we demonstrated that KHSRP directly interacts with splicing factor 3b subunit 1 (SF3B1) and enhances the binding of SF3B1 to the intronic branch sites, thereby promoting pre-mRNA splicing. Using splicing inhibitors, we found that Khsrp protects against ALF by regulating pre-mRNA splicing in vivo. Overall, our findings demonstrate that KHSRP is an important splicing activator and promotes the expression of genes associated with ALF progression by interacting with SF3B1; thus, KHSRP could be a possible target for therapeutic intervention in ALF.

Cell Death and DiseaseVol. 15(8)
Hubei University of Medicine (CN), Union Hospital (HK), Wuhan University (CN), Hubei University of Science and Technology (CN), Huazhong University of Science and Technology (CN), Hubei University (CN)
National Natural Science Foundation of China, Wuhan University
Good health and well-being
Openalex Percentile: Top 26%
RNA Research and Splicing
0.94
DOIOpen Access PDFOpenAlex
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